Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic alterations are frequently observed in all human cancers, yet how aberrant epigenetic signatures are established is poorly understood. Here we show that the gene encoding BAZ2A (TIP5), a factor previously implicated in epigenetic rRNA gene silencing, is overexpressed in prostate cancer and is paradoxically involved in maintaining prostate cancer cell growth, a feature specific to cancer cells. BAZ2A regulates numerous protein-coding genes and directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis. BAZ2A overexpression is tightly associated with a molecular subtype displaying a CpG island methylator phenotype (CIMP). Finally, high BAZ2A levels serve as an independent predictor of biochemical recurrence in a cohort of 7,682 individuals with prostate cancer. This work identifies a new aberrant role for the epigenetic regulator BAZ2A, which can also serve as a useful marker for metastatic potential in prostate cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Gene Expression Omnibus


  1. 1.

    et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

  2. 2.

    et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23, 159–170 (2013).

  3. 3.

    et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet. 14, 765–780 (2013).

  4. 4.

    et al. Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer. Genome Res. 21, 1028–1041 (2011).

  5. 5.

    et al. Altered DNA methylation landscapes of polycomb-repressed loci are associated with prostate cancer progression and ERG oncogene expression in prostate cancer. Clin. Cancer Res. 19, 3450–3461 (2013).

  6. 6.

    et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci. Transl. Med. 5, 169ra10 (2013).

  7. 7.

    et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

  8. 8.

    et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).

  9. 9.

    et al. Expression of the polycomb group protein EZH2 and its relation to outcome in patients with urothelial carcinoma of the bladder. J. Cancer Res. Clin. Oncol. 134, 331–336 (2008).

  10. 10.

    et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 24, 268–273 (2006).

  11. 11.

    et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 100, 11606–11611 (2003).

  12. 12.

    , , & Polycomb genes and cancer: time for clinical application? Crit. Rev. Oncol. Hematol. 83, 184–193 (2012).

  13. 13.

    & Epigenetic regulation of signaling pathways in cancer: role of the histone methyltransferase EZH2. J. Gastroenterol. Hepatol. 26, 19–27 (2011).

  14. 14.

    , & Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis. 2, e204 (2011).

  15. 15.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  16. 16.

    et al. TMPRSS2-ERG–specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer 11, 507 (2011).

  17. 17.

    , & The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat. Genet. 32, 393–396 (2002).

  18. 18.

    , & The chromatin remodeling complex NoRC targets HDAC1 to the ribosomal gene promoter and represses RNA polymerase I transcription. EMBO J. 21, 4632–4640 (2002).

  19. 19.

    , , , & Inheritance of silent rDNA chromatin is mediated by PARP1 via noncoding RNA. Mol. Cell 45, 790–800 (2012).

  20. 20.

    , , , & The nucleolus: an emerging target for cancer therapy. Trends Mol. Med. 19, 643–654 (2013).

  21. 21.

    et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer–specific activation of p53. Cancer Cell 22, 51–65 (2012).

  22. 22.

    et al. MiRGator v3.0: a microRNA portal for deep sequencing, expression profiling and mRNA targeting. Nucleic Acids Res. 41, D252–D257 (2013).

  23. 23.

    et al. MiR-133a inhibits colorectal cancer cell growth by direct targeting E3 ubiquitin ligase RFFL and activating p53-p21CIP1/WAF1 pathway. Gastroenterology 142, S185 (2012).

  24. 24.

    et al. MiR-133a induces apoptosis through direct regulation of GSTP1 in bladder cancer cell lines. Urol. Oncol. 31, 115–123 (2013).

  25. 25.

    et al. MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting Bcl-xL and Mcl-1. Bone 56, 220–226 (2013).

  26. 26.

    et al. MicroRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor. Oncol. Rep. 27, 1967–1975 (2012).

  27. 27.

    et al. Tumor suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer. Eur. Urol. Suppl. 106, 405–413 (2012).

  28. 28.

    , , & The chromatin remodeling complex NoRC controls replication timing of rRNA genes. EMBO J. 24, 120–127 (2005).

  29. 29.

    , & Epigenetic engineering of ribosomal RNA genes enhances protein production. PLoS ONE 4, e6653 (2009).

  30. 30.

    et al. The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats. EMBO J. 29, 2135–2146 (2010).

  31. 31.

    Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 17, 1691–1702 (2003).

  32. 32.

    , , , & PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res. 68, 1820–1825 (2008).

  33. 33.

    et al. Isolation and enrichment of PC-3 prostate cancer stem-like cells using MACS and serum-free medium. Oncol. Lett. 5, 787–792 (2013).

  34. 34.

    & PC3 prostate tumor–initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis. Mol. Cancer 9, 319 (2010).

  35. 35.

    , , & Aldehyde dehydrogenase activity selects for the holoclone phenotype in prostate cancer cells. Biochem. Biophys. Res. Commun. 414, 801–807 (2011).

  36. 36.

    , , , & Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).

  37. 37.

    et al. A molecular signature predictive of indolent prostate cancer. Sci. Transl. Med. 5, 202ra122 (2013).

  38. 38.

    et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004).

  39. 39.

    et al. Survey of differentially methylated promoters in prostate cancer cell lines. Neoplasia 7, 748–760 (2005).

  40. 40.

    et al. Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning. Endocr. Relat. Cancer 18, 465–478 (2011).

  41. 41.

    , , & Differently regulated androgen receptor transcriptional complex in prostate cancer compared with normal prostate. Int. J. Urol. 12, 390–397 (2005).

  42. 42.

    et al. Epigenetic inactivation of the HOXA gene cluster in breast cancer. Cancer Res. 66, 10664–10670 (2006).

  43. 43.

    , & ZNF185, an actin-cytoskeleton-associated growth inhibitory LIM protein in prostate cancer. Oncogene 26, 111–122 (2007).

  44. 44.

    et al. Growth inhibitory effect of Kruppel-like factor 6 on human prostatic carcinoma and renal carcinoma cell lines. Tohoku J. Exp. Med. 216, 35–45 (2008).

  45. 45.

    et al. Screening and identification of distant metastasis-related differentially expressed genes in human squamous cell lung carcinoma. Anat. Rec. (Hoboken) 295, 748–757 (2012).

  46. 46.

    , & SWAN: subset-quantile within array normalization for Illumina Infinium HumanMethylation450 BeadChips. Genome Biol. 13, R44 (2012).

  47. 47.

    et al. Cytidine methylation of regulatory sequences near the π-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc. Natl. Acad. Sci. USA 91, 11733–11737 (1994).

  48. 48.

    et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell 17, 443–454 (2010).

  49. 49.

    CpG island methylator phenotype in cancer. Nat. Rev. Cancer 4, 988–993 (2004).

  50. 50.

    et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci. Transl. Med. 4, 156ra140 (2012).

  51. 51.

    , & A multifactorial signature of DNA sequence and polycomb binding predicts aberrant CpG island methylation. Cancer Res. 69, 282–291 (2009).

  52. 52.

    et al. Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features. J. Pathol. 211, 269–277 (2007).

  53. 53.

    et al. Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth. Prostate 70, 190–199 (2010).

  54. 54.

    et al. Gata3 antagonizes cancer progression in Pten-deficient prostates. Hum. Mol. Genet. 22, 2400–2410 (2013).

  55. 55.

    & Wnt/β-catenin signalling in prostate cancer. Nat. Rev. Urol. 9, 418–428 (2012).

  56. 56.

    et al. Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness. Am. J. Transl. Res. 4, 432–442 (2012).

  57. 57.

    et al. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res. 71, 1956–1967 (2011).

  58. 58.

    et al. Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells. Oncogene 32, 4130–4138 (2013).

  59. 59.

    , & Targeting epigenetic readers in cancer. N. Engl. J. Med. 367, 647–657 (2012).

  60. 60.

    & The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr. Biol. 15, 1434–1438 (2005).

  61. 61.

    & RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

  62. 62.

    et al. An RNAi screen identifies USP2 as a factor required for TNF-α–induced NF-κB signaling. Int. J. Cancer 129, 607–618 (2011).

  63. 63.

    Analysis of chromatin composition of repetitive sequences: the ChIP-Chop assay. Methods Mol. Biol. 1094, 319–328 (2014).

  64. 64.

    , , , & GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics 23, 3251–3253 (2007).

  65. 65.

    et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod. Pathol. 21, 1371–1378 (2008).

  66. 66.

    & Recipient block TMA technique. Methods Mol. Biol. 664, 37–44 (2010).

  67. 67.

    et al. High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate 71, 281–288 (2011).

  68. 68.

    et al. Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTEN-deleted ERG fusion–positive prostate cancers with early biochemical recurrence. Mod. Pathol. 26, 733–742 (2013).

  69. 69.

    et al. Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers. Int. J. Cancer 132, 1333–1340 (2013).

Download references


We acknowledge the entire team of the German ICGC Project on Early Onset Prostate Cancer. We thank M. Lupien, C. Schmidt, D. Wuttig, O. Bogatyrova, A. Postępska-Igielska and N. Schmitt for assistance with experiments and data. This project was supported by the German Federal Ministry of Education and Science in the Program for Medical Genome Research including the EOPC project within ICGC (FKZ; 01KU1001A, 01KU1001B, 01KU1001C, 01KU1001D and 01GS0890), by Krebsforschung Schweiz (KFS; 02732-02-2011), by the Swiss National Science Foundation (SNF; 310003A-135801 and 31003A-152854), by Swiss Life, by a Müller Molecular Life Science fellowship and by Mäxi Stiftung. We acknowledge assistance provided by the Genomics and Proteomics Core Facility at the German Cancer Research Center. In particular, we acknowledge the excellent technical support of M. Schick.

Author information

Author notes

    • Lei Gu

    Present addresses: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA and Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Lei Gu
    • , Sandra C Frommel
    • , Christopher C Oakes
    •  & Ronald Simon

    These authors contributed equally to this work.

    • Guido Sauter
    • , Roland Eils
    • , Christoph Plass
    •  & Raffaella Santoro

    These authors jointly supervised this work.


  1. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Lei Gu
    • , Zuguang Gu
    • , Benedikt Brors
    •  & Roland Eils
  2. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Lei Gu
    • , Christopher C Oakes
    • , Constance Baer
    • , Melanie Weiss
    •  & Christoph Plass
  3. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.

    • Sandra C Frommel
    • , Cristina Y Gerig
    • , Dominik Bär
    •  & Raffaella Santoro
  4. Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland.

    • Sandra C Frommel
  5. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Ronald Simon
    • , Katharina Grupp
    •  & Guido Sauter
  6. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

    • Mark D Robinson
  7. Swiss Institute of Bioinformatics (SIB), University of Zurich, Zurich, Switzerland.

    • Mark D Robinson
  8. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

    • Matthieu Schapira
  9. Unit of Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center of Tumour Diseases, Heidelberg, Germany.

    • Ruprecht Kuner
    •  & Holger Sültmann
  10. Oncology Research Unit, Division of Urology, University Hospital of Zurich, Zurich, Switzerland.

    • Maurizio Provenzano
  11. Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Marie-Laure Yaspo
  12. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

    • Jan Korbel
  13. Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Thorsten Schlomm
  14. Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.

    • Roland Eils


  1. ICGC Project on Early Onset Prostate Cancer

    A list of contributing members and affiliations appears in the Supplementary Note.


  1. Search for Lei Gu in:

  2. Search for Sandra C Frommel in:

  3. Search for Christopher C Oakes in:

  4. Search for Ronald Simon in:

  5. Search for Katharina Grupp in:

  6. Search for Cristina Y Gerig in:

  7. Search for Dominik Bär in:

  8. Search for Mark D Robinson in:

  9. Search for Constance Baer in:

  10. Search for Melanie Weiss in:

  11. Search for Zuguang Gu in:

  12. Search for Matthieu Schapira in:

  13. Search for Ruprecht Kuner in:

  14. Search for Holger Sültmann in:

  15. Search for Maurizio Provenzano in:

  16. Search for Marie-Laure Yaspo in:

  17. Search for Benedikt Brors in:

  18. Search for Jan Korbel in:

  19. Search for Thorsten Schlomm in:

  20. Search for Guido Sauter in:

  21. Search for Roland Eils in:

  22. Search for Christoph Plass in:

  23. Search for Raffaella Santoro in:


L.G., S.C.F., C.C.O., R. Simon, K.G., C.Y.G., D.B., M.P., C.B., M.W. and R.K. designed the experiments and performed experimental work. L.G., R.E., C.C.O., R. Simon, Z.G., R.K., M.D.R., M.S. and K.G. performed data analysis. R.K., G.S. and H.S. provided clinical samples or data. L.G., S.C.F., C.C.O., R. Simon, C.P., G.S., R.E. and R. Santoro prepared the manuscript and figures. M.-L.Y., B.B., J.K., T.S., G.S., R.E., H.S., C.P. and R. Santoro provided project leadership. All authors contributed to the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Guido Sauter or Roland Eils or Christoph Plass or Raffaella Santoro.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14, Supplementary Tables 2, 5 and 8–13, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Expression of epigenetic regulators in prostate tumors. Related to Figure 1a. (a) List of 709 genes associated with epigenetic regulation3. (b) Expression differences of epigenetic regulators between normal prostate and prostate tumor samples.

  2. 2.

    Supplementary Table 3

    Gene expression analysis of PC3 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3. Genes upregulated or downregulated by siRNA-BAZ2A, siRNA-EZH2 or both are shown. The list of RBEPM genes is included in the list of genes upregulated by BAZ2A or EZH2 depletion.

  3. 3.

    Supplementary Table 4

    Gene expression analysis of RWPE1 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3. Genes upregulated or downregulated by siRNA-BAZ2A, siRNA-EZH2 or both are shown.

  4. 4.

    Supplementary Table 6

    Genes regulated in both PC3 and RWPE1 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3.

  5. 5.

    Supplementary Table 7

    List of differentially methylated genes in BAZ2A-high versus BAZ2A-low tumors. Related to Figure 5.

About this article

Publication history






Further reading